The use of dispersion systems as carriers of biologically active compounds is well known in the art. These systems are designed to protect the biologically active compound from the environment during delivery and to provide a controlled release of the substance to a targeted area. In some cases, the goal is to target specific sites in the body using the dispersion. Alternatively, the drug carrier system acts as a reservoir at the site of injection.
Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions. Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns dispersed in an aqueous or non-aqueous medium using suspending agents. Solid particles include microspheres, microcapsules, nanoparticles and nanospheres.
Emulsions are defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Despite their long history, emulsions are used less often today than other dosage forms due to their inherent instability. Emulsion formulations include water-in-oil and oil-in-water emulsions, multiple water/oil/water emulsions, microemulsions, microdroplets, and liposomes.
A microemulsion is a transparent or substantially transparent emulsion which is formed spontaneously or substantially spontaneously when its components are brought into contact. Microemulsions are thermodynamically stable and contain dispersed particles or droplets of a diameter less than about 200 nm, more preferably less than about 150 nm. These particles may be spherical, although other structures are possible, such as liquid crystals with lamellar, hexagonal or isotropic symmetries.
Microemulsions can also be used as a “microemulsion preconcentrate”, defined herein as a composition which spontaneously forms a microemulsion in an aqueous medium, for example in water, upon dilution, or in the gastric juices after oral application. The microemulsion can be diluted in water at a ratio of about 1:1 to about 1:10 by volume.
While emulsion-based delivery systems are useful for certain applications, the delivery vesicles are subject to physical rupture because of the delicate nature of the liquid/membrane/liquid structure. Emulsion based delivery systems also have relatively short release times. Further, it is difficult to isolate emulsion based vesicles from the aqueous media used for storage for subsequent reconstitution.
In spite of these difficulties, microemulsions have been used as successful delivery systems for certain types of pharmaceutical compounds, particularly compounds such as members of the cyclosporin class, which are cyclic oligopeptides. This carrier generally contains a hydrophilic solvent, such as liquid polyethylene glycol (PEG) 200-600, ethylene or propylene glycol, ethanol or propanol, glycerin, water, soluble fatty acid C6-C18 esters of sucrose, dimethylisosorbide, ethyl-acetate, glycofurol (fatty acid derivative of a cyclic polyol), PEG derivatives of tocopherol, or PEG-fatty acid esters; and a surfactant, such as TWEEN™ 20 (ICI Americas, Inc.) which is polyoxyethylene sorbitan monolaureate. Other ingredients include various PEG (polyethylene glycol) derivatives or phospholipids; a water-insoluble oil such as corn oil, other oils from plants and mixtures of oils; and CREMOPHOR® (BASF Corp.), which is ethoxylated castor oil and similar PEG derivatives of castor oil or other fats which are used as an amphiphilic solvent, emulsifier, surfactant, etc.
The microemulsions described above are typically droplets of oily material dispersed in water. Liquid droplets have limited stability and may rupture in response to changes in pH, ionic strength, or temperature.
It is therefore an object of then invention to provide microemulsions with increased stability.
It is another object of the invention to provide methods for the preparation of microemulsions with increased stability.
It is yet another object of the invention to provide methods of using microemulsions with increased stability in medical and non-medical applications.